The penicillins ciclacillin and dicloxacillin demonstrate marked similarities in biological activity but, as far as can be determined, differ substantially in respect to the degree of protein binding, which is relatively low for ciclacillin and relatively high for dicloxacillin. In mice infected with Staphylococcus aureus Smith, ciclacillin is considerably more active than dicloxacillin, although both drugs are similarly effective in vitro and similarly absorbed and eliminated in vivo. The high degree of protein binding exhibited by dicloxacillin could therefore very probably explain its relatively low chemotherapeutic activity. Moreover, the in vitro and in vivo findings of the study are inconsistent with the tenets of the τ/2 thesis